Combinations of stimulant laxatives and stool softeners are known on the market. For example, co-danthramer capsules and suspensions contain danthron and poloxamer (polyoxyethylene-polyoxypropylene block copolymers), and co-docusate capsules contain danthron and docusate sodium. These products have been effective in treating constipation, especially in the elderly and in patients suffering constipation resulting from administration of opioid analgesics. Such combination products have a reputation of being effective yet gentle. However the regulatory authorities have increasingly scrutinised the safety of stimulant laxatives and have restricted the indications of danthron-containing laxatives to cancer patients. Preparations containing phenolphthalein have been removed from many markets due to concern over potential carcinogenicity. Carcinogenicity testing has been conducted or is in progress with other stimulant laxatives and it is likely that other molecules will be subject to restriction of indications or removal from the market.
Bisacodyl is a diphenylmethane stimulant laxative used for the treatment of constipation and bowel evacuation. It acts mainly in the large intestine within 6-12 hours following oral administration. Bisacodyl was recently subjected to carcinogenicity testing and was shown to be free of carcinogenic/mutagenic potential and therefore, from a safety perspective, is the stimulant laxative of choice. However bisacodyl is directly irritant to the intestinal mucosa of the upper intestine and can cause griping and epigastric pain. To reduce the incidence of such effects bisacodyl is conventionally administered as enteric-coated tablets (e.g. Dulcolax, Boehringer), in doses of 5-15 mg daily. Due to the reported irritant nature of the active compound and the drug sensitivity to the low pH of the gastric environment, tablets have to be swallowed whole and not within one hour of milk or antacids. Bisacodyl is also available as suppositories, with onset of action within 20-60 minutes, but not as a commercially available oral liquid or sachet.
The enteric coated dosage forms do not lend themselves to combination products. A combination product of enteric coated bisacodyl with poloxamer is particularly difficult since the latter is a high dose, waxy, low melting point solid, which cannot be readily formulated into a solid dosage form of suitable size for acceptance by the patient.
A bisacodyl combination formulation can be made by the method of our EP-A 642,786, which involves melting a normally solid stool softener, such as a poloxamer, dispersing/dissolving the bisacodyl or other stimulant laxative in the melt, filling capsule shells, and allowing the capsules to cool. Such a product will have advantages with regard to dosage form and other properties. However, we have unexpectedly found that bisacodyl is unstable in poloxamer and also that the bisacodyl and poloxamer interact, with the degradation of the bisacodyl being accelerated in the presence of poloxamer. Preparation of capsules containing a hot melt of bisacodyl and poloxamer (as used for co-danthramer capsules), which are then enteric coated is therefore unlikely to produce a product that is chemically stable and has a satisfactory shelf life. Furthermore production scale enteric coating of capsules containing a low melting point, waxy, solid is very difficult due to melting and leakage or softening and deformation of the waxy, low melting point poloxamer.